Schizophrenia is a major public health burden affecting about 0.5% of the population. The etiology, pathogenesis, and pathophysiology of the disease is poorly understood. Current treatments help only some affected individuals and have serious side effects.Here we propose to take advantage of a major breakthrough in stem cell technology, the capacity to generate pluripotent stem cells from somatic cells such as fibroblasts, to develop novel cellular tools to help find better treatments for schizophrenia. We hypothesize that neuronal cells differentiated from pluripotent stem cells that have been derived from fibroblasts of schizophrenia patients will demonstrate abnormalities similar to the pathological and immunopathological findings detected in schizophrenia postmortem brain. To test this hypothesis, we have assembled a team with expertise in schizophrenia, stem cells, neuronal development and differentiation, and cell models of neuropsychiatric disease. In aim 1, we will carefully select and characterize 8 patients with schizophrenia and 8 matched controls, and obtain skin biopsies from them. These individuals will all have agreed to participate in extensive diagnostic interviews, as well as other protocols involving neuroimaging, genetic analysis, and neuropsychological testing. In Aim 2, we will generate fibroblast cell lines form the skin biopsies, and then use retroviruses containing human Oc3/4, Sox2, Klf4, and c-Myc to generate pluripotent stem cells from the fibroblasts. The pluripotency of the cells will be definitively established, and the cells will be differentiated into neurons. In Aim 3, we will characterize the neurons and compare the properties of cells derived from patients and from controls. We will emphasize neuritic morphology and synaptic markers, and particularly indicators of glutamatergic and GABAergic functions. The pilot data we obtain from this study will enable us to compete for funds to enlarge this enterprise, with more patients and a more systematic examination of differentiated neurons. Overall, cell lines that recapitulate aspects of the pathology of schizophrenia will serve as valuable tools in the development of new therapeutic targets for schizophrenia treatment. The cell lines may also prove of value as platforms for screening the effectiveness of new therapeutic agen. PUBLICE HEALTH REVELANCE: Our proposal is designed to generate stem cells, and subsequently neurons, from skin cells of individuals with schizophrenia, and to determine how these cells are different from cells obtained from healthy individuals. The cells will provide a valuable tool to improve our understanding of the biology of schizophrenia, and thereby of detecting new therapeutic targets for which drugs or other forms of treatment can be designed. The cells may also prove directly useful as platforms for screening existing compounds as possible therapeutic agents for schizophrenia.